Therapeutic compounds

ABSTRACT

Disclosed herein is a compound having a structure  
                 
or a pharmaceutically acceptable salt, or a prodrug thereof. Therapeutic methods, compositions, and medicaments related thereto are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/747,490, filed on MAY 11, 2007, incorporated herein byreference, which is based, and claims priority under 35 U.S.C. § 120 toU.S. Provisional Patent Application No. 60/803,040, filed on May 24,2006, and which is incorporated here by reference.

DESCRIPTION OF THE INVENTION

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Disclosed herein is a compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein Y is an organic acid functional group, or an amide or esterthereof comprising up to 14 carbon atoms; or Y is hydroxymethyl or anether thereof comprising up to 14 carbon atoms; or Y is a tetrazolylfunctional group;A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O;J is C═O, CHOH, CHF, CHCl, CHBr, or CHCN; andB is substituted aryl or substituted heteroaryl.

Also disclosed herein is a carboxylic acid or a bioisostere thereof,said carboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—,wherein 1 or 2 carbon atoms may be replaced by S or O; or A is—(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein oneCH₂ may be replaced by S or O;J is C═O, CHOH, CHF, CHCl, CHBr, or CHCN; andB is substituted aryl or substituted heteroaryl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a method of preparing compound 1d.

FIG. 2 depicts a method of preparing compound 2e.

FIG. 3 depicts a method of preparing compound 3h.

FIG. 4 depicts a method of preparing compound 4f.

FIG. 5 depicts a method of preparing compound 5e.

DETAILED DESCRIPTION OF THE INVENTION

“Bioisosteres are substituents or groups that have chemical or physicalsimilarities, and which produce broadly similar biological properties.”Silverman, Richard B., The Organic Chemistry of Drug Design and DrugAction, 2nd Edition, Amsterdam: Elsevier Academic Press, 2004, p. 29.

While not intending to be limiting, organic acid functional groups arebioisoteres of carboxylic acids. An organic acid functional group is anacidic functional group on an organic molecule. While not intending tobe limiting, organic acid functional groups may comprise an oxide ofcarbon, sulfur, or phosphorous. Thus, while not intending to limit thescope of the invention in any way, in certain compounds Y is acarboxylic acid, sulfonic acid, or phosphonic acid functional group.

Additionally, an amide or ester of one of the organic acids shown abovecomprising up to 14 carbon atoms is also contemplated. In an ester, ahydrocarbyl moiety replaces a hydrogen atom of an acid such as in acarboxylic acid ester, e.g. CO₂Me, CO₂Et, etc.

In an amide, an amine group replaces an OH of the acid. Examples ofamides include CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, and CONH(CH₂CH₂OH)where R² is independently H, C₁-C₆ alkyl, phenyl, or biphenyl. Moietiessuch as CONHSO₂R² are also amides of the carboxylic acid notwithstandingthe fact that they may also be considered to be amides of the sulfonicacid R²—SO₃H. The following amides are also specifically contemplated,CONSO₂-biphenyl, CONSO₂-phenyl, CONSO₂-heteroaryl, and CONSO₂-naphthyl.The biphenyl, phenyl, heteroaryl, or naphthyl may be substituted orunsubstituted.

Han et. al. (Biorganic & Medicinal Chemistry Letters 15 (2005)3487-3490) has recently shown that the groups shown below are suitablebioisosteres for a carboxylic acid. The activity of compounds with thesegroups in inhibiting HCV NS3 protease was comparable to or superior tosimilar compounds where the group is replaced by CO₂H. Thus, Y could beany group depicted below.Carboxylic Acid Bioisosteres According to Han et al.

While not intending to limit the scope of the invention in any way, Ymay also be hydroxymethyl or an ether thereof comprising up to 14 carbonatoms. An ether is a functional group wherein a hydrogen of an hydroxylis replaced by carbon, e.g., Y is CH₂OCH₃, CH₂OCH₂CH₃, etc. These groupsare also bioisosteres of a carboxylic acid.

“Up to 14 carbon atoms” means that the entire Y moiety, including thecarbonyl carbon of a carboxylic acid ester or amide, and both carbonatoms in the —CH₂O—C of an ether has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 carbon atoms.

Finally, while not intending to limit the scope of the invention in anyway, Y may be a tetrazolyl functional group.

While not intending to be limiting, examples of compounds having theidentified Y are depicted below. In these examples R is H orhydrocarbyl, subject to the constraints defined herein. Each structurebelow represents a specific embodiment which is individuallycontemplated, as well as pharmaceutically acceptable salts and prodrugsof compounds which are represented by the structures. However, otherexamples are possible which may not fall within the scope of thestructures shown below.

Organic Acids Esters Amides

A tetrazolyl functional group is another bioisostere of a carboxylicacid. An unsubstituted tetrazolyl functional group has two tautomericforms, which can rapidly interconvert in aqueous or biological media,and are thus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, unsubstituted and hydrocarbyl substituted tetrazolyl upto C₁₂ are considered to be within the scope of the term “tetrazolyl.”

While not intending to limit the scope of the invention in any way, inone embodiment, Y is CO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂,CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

According to Silverman (p. 30), the moieties shown below are alsobioisosteres of a carboxylic acid.Carboxylic Acid Bioisosteres According to Silverman

Orlek et al. (J. Med. Chem. 1991, 34, 2726-2735) described oxadiazolesas suitable bioisosteres for a carboxylic acid. These ester replacementswere shown to be potent muscarinic agonists having improved metabolicstability. Oxadiazoles were also described by Anderson et al. (Eur. J.Med. Chem. 1996, 31, 417-425) as carboxamide replacements havingimproved in vivo efficacy at the benzodiazepine receptor.Carboxylic Acid Bioisosteres According to Orlek et. al.

Kohara et al. (J. Med. Chem. 1996, 39, 5228-5235) described acidicheterocycles as suitable bioisosteres for a tetrazole. These carboxylicacid replacements were shown to be potent angiotensin II receptorantagonists having improved metabolic stability.Tetrazole Bioisosteres According to Kohara et. al.

Drysdale et al. (J. Med. Chem. 1992, 35, 2573-2581) have describedcarboxylic acid mimics of non-peptide CCK—B receptor antagonists. Thebinding affinities of many of the bioisosteres are similar to the parentcarboxylic acid.Carboxylic Acid Bioisosteres According to Drysdale et. al.

In relation to the identity of A disclosed in the chemical structurespresented herein, A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein oneCH₂ may be replaced with S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S and/or O. For example,while not intending to limit the scope of the invention in any way, Amay be a moiety where S replaces one or two carbon atoms such as one ofthe following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be a moiety where O replaces one or two carbon atomssuch as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have an O replacing one carbon atom and an S replacinganother carbon atom, such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(n)— whereinAr is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3,or 4, and wherein one CH₂ may be replaced with S or O. In other words,while not intending to limit the scope of the invention in any way,

in one embodiment A comprises 1, 2, 3, or 4 CH₂ moieties and Ar, e.g.—CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂Ar—(CH₂)₂—, —(CH₂)₂—Ar—(CH₂)₂—,and the like;

in another embodiment A comprises: O; 0, 1, 2, or 3 CH₂ moieties; andAr, e.g., —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—,—O—CH₂—Ar—(CH₂)₂, and the like; or

in another embodiment A comprises: S; 0, 1, 2, or 3 CH₂ moieties; andAr, e.g., —S—Ar—, Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—,—S—CH₂—Ar—(CH₂)₂, —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂—Ph—. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, wherein the heavy atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. Any number of hydrogen atoms required for aparticular substituent will also be included. A substituent must bestable enough for the compound to be useful as described herein. Inaddition to the atoms listed above, a substituent may also have a metalcation or any other stable cation having an atom not listed above if thesubstituent is acidic and the salt form is stable. For example, —OH mayform an —O—Na⁺ salt or CO₂H may form a CO₂—K⁺ salt.

Any cation of the salt is not counted in the “4 or less heavy atoms.”Thus, the substituent may be

hydrocarbyl having up to 4 carbon atoms, including alkyl up to C₄,alkenyl, alkynyl, and the like;

hydrocarbyloxy up to C₃;

organic acid such as CO₂H, SO₃H, P(O)(OH)₂, and the like, and saltsthereof;

CF₃;

halo, such as F, Cl, or Br;

hydroxyl;

NH₂ and alkylamine functional groups up to C₃;

other N or S containing substituents such as CN, NO₂, and the like;

and the like.

In one embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterphenylene, the sum of m and o is 1, 2, or 3, and wherein one CH₂may be replaced with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂—Ar—OCH₂— and Ar is interphenylene. In another embodiment, Ar isattached at the 1 and 3 positions, otherwise known as m-interphenylene,such as when A has the structure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂—Ph-wherein one CH₂ may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂—Ph—.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂—O—(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)₃—.

In another embodiment A is —CH₂—Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl.

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

In another embodiment, A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4,and wherein one CH₂ may be replaced by S or O.

In another embodiment, A is —(CH₂)₃Ar—, —O(CH₂)₂Ar—, —CH₂OCH₂Ar—,—(CH₂)₂OAr, —O(CH₂)₂Ar—, —CH₂OCH₂Ar—, or —(CH₂)₂OAr, wherein Ar ismonocyclic interheteroarylene.

In another embodiment, Ar is interthienylene.

In another embodiment, Ar is interthiazolylene.

In another embodiment, Ar is interoxazolylene.

In another embodiment, A is 6-hexyl.

In another embodiment, A is (Z)-6-hex-4-enyl.

Compounds according to the each of the structures depicted below, andpharmaceutically acceptable salts thereof, and prodrugs thereof, arecontemplated as individual embodiments. In other words, each structurerepresents a different embodiment.

J is C═O, CHOH, CHF, CHCl, CHBr, or CHCN. Thus, each structure depictedbelow represents a compound embodiment which is individuallycontemplated. Pharmaceutically acceptable salts and prodrugs ofcompounds according to the structures below are also contemplated.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.one or more ring carbons are substituted by N, O, and/or S. While notintending to be limiting, examples of heteroaryl include thienyl,pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, andthe like.

A substituent of aryl or heteroaryl may have up to 20 non-hydrogen atomseach in any stable combination and as many hydrogen atoms as necessary,wherein the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. However, the total number of non-hydrogen atomson all of the substituents combined must also be 20 or less. Asubstituent must be sufficiently stable for the compound to be useful asdescribed herein. In addition to the atoms listed above, a substituentmay also have a metal cation or other stable cation having an atom notlisted above if the substituent is acidic and the salt form is stable.For example, —OH may form an —O—Na⁺ salt or CO₂H may form a CO₂—K⁺ salt.Thus, while not intending to limit the scope of the invention in anyway, a substituent may be:

hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen suchas alkyl, alkenyl, alkynyl, and the like, including linear, branched orcyclic hydrocarbyl, and combinations thereof;

hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,O-cyclohexyl, etc, up to 19 carbon atoms;

other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the like;

thioether substituents including S-hydrocarbyl and other thioethersubstituents;

hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,etc, up to 19 carbon atoms;

nitrogen substituents such as NO₂, CN, and the like, including

amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like up to 19 carbonatoms;

carbonyl substituents, such as CO₂H, ester, amide, and the like;

halogen, such as chloro, fluoro, bromo, and the like

fluorocarbyl, such as CF₃, CF₂CF₃, etc.;

phosphorous substituents, such as PO₃ ²⁻, and the like;

sulfur substituents, including S-hydrocarbyl, SH, SO₃H, SO₂-hydrocarbyl,SO₃-hydrocarbyl, and the like.

Substituted aryl or heteroaryl may have as many substituents as the ringor ring system will bear, and the substituents may be the same ordifferent. Thus, for example, an aryl ring or a heteroaryl ring may besubstituted with chloro and methyl; methyl, OH, and F; CN, NO₂, andethyl; and the like including any conceivable substituent or combinationof substituent possible in light of this disclosure.

Substituted aryl or substituted heteroaryl also includes a bicyclic orpolycyclic ring system wherein one or more rings are aromatic and one ormore rings are not. For example, indanonyl, indanyl, indanolyl,tetralonyl, and the like are substituted aryl. For this type ofpolycyclic ring system, an aromatic or heteroaromatic ring, not anon-aromatic ring, must be attached to the remainder of the molecule. Inother words, in any structure depicting —B herein, where — is a bond,the bond is a direct bond to an aromatic ring.

In one embodiment, B is substituted aryl or heteroaryl.

In another embodiment B is substituted phenyl.

In another embodiment B has no halogen atoms.

In another embodiment B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxybutyl)phenyl.

In another embodiment B is 4-(1-hydroxyheptyl)phenyl.

In another embodiment B is 4-(1-hydroxyhexyl)phenyl.

In another embodiment B is 4-(1-hydroxypentyl)phenyl.

In another embodiment B is 4-(1-hydroxypropyl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

In another embodiment B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 3-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

In another embodiment B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-tert-butylphenyl.

In another embodiment B is 4-hexylphenyl.

In another embodiment B is 4-(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxycyclobutyl)phenyl.

In another embodiment B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

In another embodiment B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

In another embodiment B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

In another embodiment B is 4-(cyclohexylmethyl)phenyl.

In another embodiment B is 4-(hydroxy(phenyl)methyl)phenyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.Another embodiment is a compound according to the structure

“C1-10” hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 carbon atoms.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

Alkyl is hydrocarbyl having no double or triple bonds including:

linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl,and the like;

branched alkyl such as isopropyl, branched butyl isomers (i.e.sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e. isopentyl,etc), branched hexyl isomers, and higher branched alkyl fragments;

cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc.; and

alkyl fragments consisting of both cyclic and noncyclic components,whether linear or branched, which may be attached to the remainder ofthe molecule at any available position including terminal, internal, orring carbon atoms.

Alkenyl is hydrocarbyl having one or more double bonds including

linear alkenyl, branched alkenyl, cyclic alkenyl, and combinationsthereof in analogy to alkyl.

Alkynyl is hydrocarbyl having one or more triple bonds including linearalkynyl, branched alkynyl, cyclic alkynyl and combinations thereof inanalogy to alkyl.

Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like.

Aryl may or may not be hydrocarbyl, depending upon whether it hassubstituents with heteroatoms.

Arylalkyl is alkyl which is substituted with aryl. In other words alkylconnects aryl to the remaining part of the molecule. Examples are—CH₂—Phenyl, —CH₂—CH₂—Phenyl, and the like. Arylalkyl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.

Unconjugated dienes or polyenes have one or more double bonds which arenot conjugated. They may be linear, branched, or cyclic, or acombination thereof.

Combinations of the above are also possible.

Thus, each of the structures below is contemplated. These structures, orpharmaceutically acceptable salts thereof, or prodrugs thereof,individually represent a compound which is an embodiment contemplatedherein. In other words, each structure represents a differentembodiment.

In the above embodiments, x is 5, 6, or 7, and y+z is 2x+1.

In one embodiment, x is 5 and y+z is 11.

In another embodiment, x is 6 and y+z is 13.

In another embodiment, x is 7 and y+z is 15.

Hypothetical examples of useful compounds are shown below.

COMPOUND EXAMPLES

The following are hypothetical examples of useful compounds:

Compound Example 1

A compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;wherein Y is an organic acid functional group, or an amide or esterthereof comprising up to 14 carbon atoms; or Y is hydroxymethyl or anether thereof comprising up to 14 carbon atoms; or Y is a tetrazolylfunctional group;A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O;J is C═O, CHOH, CHF, CHCl, CHBr, or CHCN; andB is substituted aryl or substituted heteroaryl.

Compound Example 2

The compound according to compound example 1 wherein Y is selected fromCO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH,P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

Compound Example 3

The compound according to compound example 1 or 2 wherein B issubstituted phenyl.

Compound Example 4

The compound according to compound example 1 or 2 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 5

The compound according to compound example 4 wherein R is alkyl.

Compound Example 6

The compound according to compound example 4 wherein R is arylalkyl.

Compound Example 7

The compound according to compound example any one of compound examples1 to 6 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 8

The compound according to compound example 1 or 2 wherein A is(3-methylphenoxy)methyl.

Compound Example 9

The compound according to compound example 1 or 2 wherein A is(4-but-2-ynyloxy)methyl.

Compound Example 10

The compound according to compound example 1 or 2 wherein A is2-(2-ethylthio)thiazol-4-yl.

Compound Example 11

The compound according to compound example 1 or 2 wherein A is2-(3-propyl)thiazol-5-yl.

Compound Example 12

The compound according to compound example 1 or 2 wherein A is3-methoxymethyl)phenyl.

Compound Example 13

The compound according to compound example 1 or 2 wherein A is3-(3-propylphenyl.

Compound Example 14

The compound according to compound example 1 or 2 wherein A is3-methylphenethyl.

Compound Example 15

The compound according to compound example 1 or 2 wherein A is4-(2-ethyl)phenyl.

Compound Example 16

The compound according to compound example 1 or 2 wherein A is4-phenethyl.

Compound Example 17

The compound according to compound example 1 or 2 wherein A is4-methoxybutyl.

Compound Example 18

The compound according to compound example 1 or 2 wherein A is5-(methoxymethyl)furan-2-yl.

Compound Example 19

The compound according to compound example 1 or 2 wherein A is5-(methoxymethyl)thiophen-2-yl.

Compound Example 20

The compound according to compound example 1 or 2 wherein A is5-(3-propyl)furan-2-yl.

Compound Example 21

The compound according to compound example 1 or 2 wherein A is5-(3-propyl)thiophen-2-yl.

Compound Example 22

The compound according to compound example 1 or 2 wherein A is 6-hexyl.

Compound Example 23

The compound according to compound example 1 or 2 wherein A is(Z)-6-hex-4-enyl.

Compound Example 24

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

Compound Example 25

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

Compound Example 26

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-methylpropyl)phenyl.

Compound Example 27

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxybutyl)phenyl.

Compound Example 28

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxyheptyl)phenyl.

Compound Example 29

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxyhexyl)phenyl.

Compound Example 30

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxypentyl)phenyl.

Compound Example 31

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxypropyl)phenyl.

Compound Example 32

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

Compound Example 33

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

Compound Example 34

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

Compound Example 35

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 2,3-dihydro-1H-inden-5-yl.

Compound Example 36

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 3-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

Compound Example 37

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

Compound Example 38

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

Compound Example 39

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-tert-butylphenyl.

Compound Example 40

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-hexylphenyl.

Compound Example 41

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-phenylethyl)phenyl.

Compound Example 42

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

Compound Example 43

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxycyclobutyl)phenyl.

Compound Example 44

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

Compound Example 45

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

Compound Example 46

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

Compound Example 47

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(cyclohexylmethyl)phenyl.

Compound Example 48

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(hydroxy(phenyl)methyl)phenyl.

The following are hypothetical examples of compositions, kits, methods,uses, and medicaments employing the hypothetical compound examples.

COMPOSITION EXAMPLE

A composition comprising a compound according to any one of compoundexamples 1 to 48, wherein said composition is a liquid which isophthalmically acceptable.

MEDICAMENT EXAMPLES

Use of a compound according to any one of compound examples 1 to 48 inthe manufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

A medicament comprising a compound according to any one of compoundexamples 1 to 48, wherein said composition is a liquid which isophthalmically acceptable.

METHOD EXAMPLE

A method comprising administering a compound according to any one ofcompound examples 1 to 48 to a mammal for the treatment of glaucoma orocular hypertension.

KIT EXAMPLE

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 48, a container, and instructions foradministration of said composition to a mammal for the treatment ofglaucoma or ocular hypertension.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts: IngredientAmount (% w/v) active ingredient about 0.001-5 preservative  0-0.10vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10   pH adjustor q.s. pH4.5-7.5 antioxidant as needed surfactant as needed purified water asneeded to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The compounds disclosed herein are also useful in combination with otherdrugs useful for the treatment of glaucoma or other conditions.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

US patent application publication 2005/0176800, expressly incorporatedherein by reference, describes the preparation of substitutedpyrrolidine derivatives 1a, 3a and 4a (see accompanying FIGS. 1-5).Pyrrolidine 1a is arylated on nitrogen using aryl halide A employingBuchwald/Hartwig reaction procedures in order to install the ω-chain(FIG. 1). Standard deprotection and saponification procedures would thenafford desired acid 1d. Arylation may be carried out using a widevariety of substituted bromophenyl and other bromoaryl compounds, whichare either available commercially or may be made according to publishedliterature procedures. For example, U.S. patent application Ser. No.11/009,298, filed on Dec. 10, 2004 and U.S. Provisional PatentApplication 60/742,779 filed on Dec. 6, 2005, both of which areexpressly incorporated by reference herein, disclose methods of making anumber of useful substituted bromophenyl compounds. These procedures mayalso be readily adapted to other bromoaryl compounds such as substitutedbromothienyl, substituted bromofuryl, substituted bromopyridinyl,substituted bromonaphthyl, substituted bromobenzothienyl, and the like.

Additionally, the hydroxyl of intermediate 1c is protected and the C-9ketone functionality is manipulated to the chloride derivative 2d (FIG.2). Standard deprotection and saponification procedures would thenafford desired acid 2e.

Compounds wherein J is CN compounds may be prepared by adapting theprocedure disclosed in U.S. Provisional Patent Application No.60/747,835, filed May 22, 2006, which is expressly incorporated byreference herein.

Compounds wherein J is CHF may be prepared by adapting the proceduresdisclosed in U.S. patent application Ser. No. 11/009,298 and U.S.Provisional Patent Application No. 60/742,779.

Compounds wherein J is CHBr may be prepared by adapting the proceduresdisclosed in Tani, K. et. al. (ONO) Bioorganic and Medicinal Chemistry2002, 10, 1883.

Alternative α-chains and ω-chains may also be envisioned by thoseskilled in the art. Thus, aldehyde 3a is reacted with known phosphoniumsalts B in a Wittig reaction (FIG. 3). The resultant olefin may beremoved by hydrogenation. Procedures described in US patent applicationpublication 2005/0176800, which is expressly incorporated by referenceherein, are then employed to arrive at intermediate 3f. Thisintermediate is subjected to conditions similar to those depicted inFIG. 1 to arrive at arylated product 3g (where B is substituted aryl orheteroaryl as described in the specification above). 3g is thenconverted into 3h according to the procedures of FIG. 2.

In one hypothetical example, pyrrolidine 4a is alkylated usingelectrophile C to afford 4b. Deprotection followed by arylation affords4d and subsequent manipulations described in FIG. 1 would then afforddesired acid 4f. Similar procedures may be carried by substituting thethienyl of C with phenyl (i.e. X—CH₂-phenyl-CO₂H) or anotherheteroaromatic ring such as furyl, pyridinyl, etc. These compounds arecommercially available, or may be readily prepared by art recognizedmethods.

In another hypothetical example, pyrrolidine 4a is oxidized using Swemoxidation conditions and then is converted into vinyl compound 5b.Grubbs' methathesis with olefin D (in accordance with the procedures ofU.S. Provisional Application No. 60/777,506, which was filed Feb. 28,2006, expressly incorporated by reference herein) affords alkene 5c.Hydrogenation, followed by manipulations described in FIG. 1 would thenafford desired acid 5e. Phenyl and other heteroaromatic rings such asthienyl, furyl, etc. may be substituted for the thienyl of D to yieldsimilar products.

SYNTHETIC EXAMPLES

US patent application publication 2005/0176800 describes the preparationof substituted pyrrolidine derivatives 1a, 3a and 4a (see accompanyingFIGS. 1-5). Pyrrolidine 1a is arylated on nitrogen using aryl halide Aemploying Buchwald/Hartwig reaction procedures in order to install the{tilde over (ω)}-chain (FIG. 1). Standard deprotection andsaponification procedures would then afford desired acid 1d.

Additionally, the hydroxyl of intermediate 1c is protected and the C-9ketone functionality is manipulated to the chloride derivative 2d (FIG.2). Standard deprotection and saponification procedures would thenafford desired acid 2e.

Alternative α-chains and {tilde over (ω)}-chains may also be envisionedby those skilled in the art. Thus, aldehyde 3a is reacted with knownphosphonium salts B in a Wittig reaction (FIG. 3). The resultant olefinmay be removed by hydrogenation. Procedures described in US patentapplication publication 2005/0176800 are then employed to arrive atintermediate 3f. This intermediate is subjected to conditions similar tothose depicted in FIG. 1 to arrive at arylated product 3g (where B issubstituted aryl or heteroaryl as described in the specification above).3g is then converted into 3h according to the procedures of FIG. 2.

Specifically, pyrrolidine 4a is alkylated using electrophile C to afford4b. Deprotection followed by arylation affords 4d and subsequentmanipulations described in FIG. 1 would then afford desired acid 4f.

Additionally, pyrrolidine 4a is oxidized using Swem oxidation conditionsand then is converted into vinyl compound 5b. Grubbs' methathesis witholefin D (in accordance with the procedures of U.S. patent applicationSer. No. 11/672,433, filed on Feb. 7, 2007) affords alkene 5c.Hydrogenation, followed by manipulations described in FIG. 1 would thenafford desired acid 5e.

Examples 1 and 25-((((2S,3R)-3-chloro-1-(4-(1-hydroxyhexyl)phenyl)pyrrolidin-2-yl)methoxy)methyl)thiophene-2-carboxylicacid (4f) and5-((((2S,3R)-3-chloro-1-(4-((E)-hex-1-enyl)phenyl)pyrrolidin-2-yl)methoxy)methyl)thiophene-2-carboxylicacid (4g)

Step 1. Alkylation of 4a to give 4b

A solution of 4a (150 mg, 0.64 mmol) and bromide C (179 mg, 0.76 mmol)in DMF (0.45 mL) and THF (1.8 mL) was cooled to between −40° C. and −20°C. Sodium hydride (51 mg, 1.27 mmol) was added portionwise over 10 min.After 1 h stirring between −40° C. and −20° C., the reaction wasquenched with water (3 mL) and extracted with CH₂Cl₂ (4×5 mL). Thecombined organic phase was dried (Na₂SO₄), filtered and concentrated invacuo. Purifcation of the crude residue on silica (hexanes:CH₂Cl₂)afforded 169 mg (68%) 4b as a pale yellow oil.

Step 2. Deprotection of 4b To Give 4c

A flask was charged with 4b (160 mg, 0.41 mmol) and 3 M HCl in1,4-dioxane (0.82 mL) to give a clear pale yellow solution. Afterstirring at rt for 3 h, the mixture was diluted with CH₂Cl₂ (5 mL) andquenched with saturated aqueous NaHCO₃ (4 mL). The phases were separatedand the aqueous phase was extracted with CH₂Cl₂ (2×2 mL). The combinedorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the crude residue on silica (MeOH:CH₂Cl₂) afforded 92 mg(77%) 4c as a pale yellow oil.

Step 3. Arylation of 4c to Give 4d

Bromide A (107 mg, 0.29 mmol), 4c (100 mg, 0.35 mmol), Pd(OAc)₂ (6.5 mg,0.029 mmol), racemic BINAP (27 mg, 0.043 mmol), cesium carbonate (131,0.40 mmol) and toluene (1.2 mL) were combined in a 12×75 mm test tube.The tube was fitted with a septum, purged with nitrogen and placed in a100° C. oil bath. After stirring for 16 h, the mixture was cooled,diluted with EtOAc and filtered through celite. The filtrate wasconcentrated in vacuo. Purification of the crude residue on silica(hexane ˜15% EtOAc/hexanes→EtOAc, gradient) afforded 51 mg (31%) 4dalong with 45 mg (45%) recovered 4c.

Step 4. Deprotection of 4d to give 4e

Tetrabutylammonium fluoride (0.26 mL of a 1.0 M solution in THF, 0.26mmol) was added to a solution of 4d (50 mg, 0.088 mmol) in THF (0.6 mL).After stirring 16 h at rt, the solvents were removed under a stream ofnitrogen and the mixture was diluted with EtOAc (20 mL). The organicphase was washed with water (3×10 mL) and brine (10 mL) then dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of the cruderesidue on silica (hexane→40% EtOAc/hexanes, gradient) afforded 13.3 mg(33%) 4e along with 11.5 mg (23%) recovered 4d.

Step 5. Saponification of 4e to Give 4f and 4g

Trial 1: Lithium hydroxide (0.05 mL of a 1.0 N solution in water, 0.05mmol) was added to a solution of ester 4e (2 mg, 0.004 mmol) in THF (0.1mL) in a 1 dram vial and the mixture was stirred overnight at rt. After16 h, the solvent was removed under a stream of nitrogen and the mixturewas diluted with water (0.2 mL) and acidified with 1.0 N HCl (0.1 mL).The mixture was extracted with EtOAc (3×2 mL). The combined extractswere washed with brine (1 mL), dried (Na₂SO₄), filtered and concentratedin vacuo to afford 1.5 mg of 4f contaminated with elimination product 4g(about 70% pure by ¹H-NMR analysis.)

Trial 2: Lithium hydroxide (0.09 mL of a 1.0 N solution in water, 0.09mmol) was added to a solution of ester 4e (8 mg, 0.017 mmol) in THF(0.17 mL) and the mixture was stirred overnight at rt. After 16 h, thesolvent was removed under a stream of nitrogen and the mixture wasdiluted with water (1 mL) and acidified with 1.0 N HCl (0.1 mL). Themixture was extracted with EtOAc (3×10 mL). The combined extracts werewashed with brine (5 mL), dried (Na₂SO₄), filtered and concentrated invacuo to afford a mixture of 4f and 4g. Purifcation of the crude mixtureon silica (CH₂Cl₂→15% MeOH/CH₂Cl₂, gradient) afforded 2.0 mg (27%) of 4g(no 4f was isolated, presumably due to decomposition on silica).

Example 35-((((2S,3R)-3-chloro-1-(4-hexanoylphenyl)pyrrolidin-2-yl)methoxy)methyl)thiophene-2-carboxylicacid (6b)

Step 1. Arylation of 4c to Give 6a

Bromide E (74 mg, 0.29 mmol), 4c (100 mg, 0.35 mmol), Pd(OAc)₂ (6.5 mg,0.029 mmol), racemic BINAP (27 mg, 0.043 mmol), cesium carbonate (131,0.40 mmol) and toluene (1.2 mL) were combined in a 12×75 mm test tube.The tube was fitted with a septum, purged with nitrogen and placed in a100° C. oil bath. After stirring 16 h, the mixture was cooled, dilutedwith EtOAc and filtered through celite. The filtrate was concentrated invacuo. Purification of the crude residue on 12g silica (hexane→15%EtOAc/hexanes→EtOAc, gradient) afforded 77 mg (57%) 6a.

Step 2. Saponification of 6a to Give 6b

Lithium hydroxide (0.23 mL of a 1.0 N solution in water, 0.23 mmol) wasadded to a solution of ester 6a (21 mg, 0.045 mmol) in THF (0.45 mL) andthe mixture was stirred overnight at rt. After 16 h, the solvent wasremoved under a stream of nitrogen and the mixture was diluted withwater (1 mL) and acidified with 0.5 N HCl (2 mL). The mixture wasextracted with EtOAc (3×10 mL). The combined extracts were washed withbrine (10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the crude mixture on silica (CH₂Cl₂→10% MeOH/CH₂Cl₂,gradient) afforded 12 mg (59%) of 6b.

In Vitro Testing

U.S. patent application Ser. No. 11/553,143, filed on Oct. 26, 2006,incorporated by reference herein, describes the methods used to obtainthe in vitro data in the tables below. TABLE 1 EP2 data EP4 data fliprcAMP flipr Other Receptors (EC50 in nM) Structure EC50 EC50 Ki EC50 KihFP hEP1 hEP3A hTP hIP hDP

2178 339 1843 NT >10000 NA NA NA NA NA NA

8419 327 3011 >10000  1495 NA NA NA NA NA NA

3813  17  85 >10000  1019 NA NA NA NA NA NA

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the claims.

1. A compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof; wherein Y is an organic acid functional group, or an amide or ester thereof comprising up to 14 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 14 carbon atoms; or Y is a tetrazolyl functional group; A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O; J is C═O, CHOH, or CHCl; and B is substituted aryl or substituted heteroaryl.
 2. The compound of claim 1 wherein Y is selected from CO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, or unsubstituted biphenyl.
 3. The compound of claim 1 wherein B is substituted phenyl.
 4. The compound of claim 2 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof; R is hydrogen or C₁₋₁₀ hydrocarbyl.
 5. The compound of claim 4 wherein R is C₁₋₁₀ alkyl.
 6. The compound of claim 5, wherein A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O.
 7. The compound of claim 6 wherein A is —(CH₂)₃Ar—, —O(CH₂)₂Ar—, —CH₂OCH₂Ar—, —(CH₂)₂OAr, —O(CH₂)₂Ar—, —CH₂OCH₂Ar—, or —(CH₂)₂OAr, wherein Ar is monocyclic interheteroarylene.
 8. The compound of claim 7 wherein Ar is interthienylene.
 9. The compound of claim 7 wherein Ar is interthiazolylene.
 10. The compound of claim 7 wherein Ar is interoxazolylene.
 11. The compound of claim 5 wherein A is 6-hexyl.
 12. The compound of claim 5 wherein A is (Z)-6-hex-4-enyl.
 13. The compound of claim 1 wherein J is C═O.
 14. The compound of claim 1 wherein J is CHOH.
 15. The compound of claim 1 wherein J is CHCl.
 16. The compound of claim 15 having a formula


17. The compound of claim 15 having a formula


18. The compound of claim 15 having a formula


19. A method comprising administering a compound of claim 1 to a mammal for the treatment of glaucoma or ocular hypertension.
 20. A composition comprising a compound of claim 1, wherein said composition is a liquid which is ophthalmically acceptable. 